Loss of Rb overrides the requirement for ERK activity for cell proliferation.
MetadataShow full item record
The Ras GTPase is a critical transducer of mitogenic signals ultimately leading to inactivation of the retinoblastoma (Rb) protein, but the molecular basis underlying Ras-dependent control of cell cycle kinetics remains to a great extent unknown. In an effort to further elucidate the role of Ras activation in cell cycle control, we have studied the role of the downstream Mek-ERK pathway in facilitating exit from the quiescent G0 state and passage through the G1/S transition. We have adopted a genetic approach in combination with U0126, an inhibitor of Mek activation to study the role of Mek in cell cycle progression. Here we report that whereas wild-type (Wt) mouse embryo fibroblasts (MEFs) depend on ERK activation to enter the cell cycle, Rb-deficient (Rb(-/-)) MEFs have a reduced requirement for ERK signalling. Indeed in the presence of U0126 we found that Rb-null MEFs can exit G0, make the G1/S transition and proliferate. Analysis of Rb-deficient tumour cell lines also revealed a reduced requirement for ERK signalling in asynchronous growth. We discuss the molecular mechanism that may underlie this escape from MAP kinase signalling.
Version of record
Tumor Cells, Cultured
Mitogen-Activated Protein Kinase Kinases
Mitogen-Activated Protein Kinases
MAP Kinase Signaling System
Gene Expression Regulation
Cyclin-Dependent Kinase 4
License start date
Journal of cell science, 2002, 115 (Pt 23), pp. 4607 - 4616
Showing items related by title, author, creator and subject.
A phase I pharmacokinetic and pharmacodynamic study of the oral mitogen-activated protein kinase kinase (MEK) inhibitor, WX-554, in patients with advanced solid tumours. Jamieson, D; Griffin, MJ; Sludden, J; Drew, Y; Cresti, N; Swales, K; Merriman, M; Allen, R; Bevan, P; Buerkle, M; Mala, C; Coyle, V; Rodgers, L; Dean, E; Greystoke, A; Banerji, U; Wilson, RH; Evans, TRJ; Anthoney, A; Ranson, M; Boddy, AV; Plummer, R (2016-11)Purpose We performed a multi-centre phase I study to assess the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of the orally available small molecule mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor, ...
Activation of either ERK1/2 or ERK5 MAP kinase pathways can lead to disruption of the actin cytoskeleton. Barros, JC; Marshall, CJ (2005-04)Oncogenic transformation often leads to the disruption of the actin cytoskeleton. Activation of the classical Ras-Raf-MEK1/2-ERK1/2 signalling cascade has been implicated in the effects of oncogenes such as Ras and Src on ...
Combined Pan-RAF and MEK Inhibition Overcomes Multiple Resistance Mechanisms to Selective RAF Inhibitors. Whittaker, SR; Cowley, GS; Wagner, S; Luo, F; Root, DE; Garraway, LA (2015-12)RAF and MEK inhibitors are effective in BRAF-mutant melanoma but not in BRAF-mutant colorectal cancer. To gain additional insights into this difference, we performed a genome-scale pooled shRNA enhancer screen in a ...